染色体不稳定性(CIN)被认为是肿瘤进程的主要驱动力，而前期我们临床发现乳头状甲状腺癌(PTC)男性复发转移率是女性的1.7倍，并且其复发转移与PTC致死密切相关因而课题组前期通过对临床样本进行蛋白芯片分析，发现组蛋白去甲基化酶Jmjd1c和转录因子HOXA10在转移组织中高表达,而切割因子CFIm25低表达;3’RACE发现高表达的Jmjd1c具有较短的3'UTR，miR34c可靶向Jmjd1c较长的3'UTR抑制其表达;序列分析发现Jmjd1c上存在CFIm25的结合位点。在此基础上,本项目拟通过CoIP、RIP、双荧光素酶报告等试验深入探讨CFIm25通过可变多聚腺苷酸化(APA)调控的Jmjd1c/HOXA10信号轴,影响CIN在PTC复发转移中的分子机制。其研究结果有望解释APA和染色质信号在PTC进程中的作用机制,为新药开发提供新的干预靶点和理论依据。

Chromosomal instability (CIN) is considered to be the main driving force of the tumor process.Previous studies have found the recurrence and metastasis rate of papillary thyroid carcinoma (PTC) of male was 1.7 times higher than that of the female. And metastasis is the main cause of death for PTC. Our previous study by protein chip found that histone demethylase Jmjd1c and transcription factor HOXA10 was highly expressed in metastatic PTC tissues, whereas cutting factor CFIm25 was lower expressed. 3 'RACE found that higher expression of Jmjd1c has a shorter 3 "UTR. Meanwhile, miR34c could bind to the longer 3’UTR to inhibit the expression of Jmjd1c. There are CFIm25 binding sites on Jmjd1c by sequence the analysis. Based on former researches, this project plans to further study CFIm25 inhibits distal polyadenylation by selective polyadenylation (APA), bring to shorter 3 'UTR of Jmjd1c, which inhibiting negative regulatory factor binding, to promote the expression of Jmjd1c, increasing the instability of chromatin through epigenetic modification of chromatin,by RIP, dual luciferase test and other molecular methods. Jmjd1c enhances HOXA10 transcriptional activity by direct combination to promote the transcription of the downstream genes through CoIP. The results are expected to explain the mechanism of APA and chromatin signals in the regulation of the PTC process, and provide new targets and theoretical basis for the development of new drugs.